Many people suffer from disorders that require long-term or life-long medical management. These diseases, whose etiologies can be infectious (e.g., viral hepatitis, human immunodeficiency virus, herpesviruses) or non-infectious (e.g., renal failure, autoimmune diseases, cancer), and the associated therapies, are often associated with fatigue, non-restorative sleep, and excessive daytime sleepiness. In addition, growing numbers of individuals suffer from debilitating chronic fatigue of undetermined etiology. Excessive sleepiness and fatigue, particularly when persistent, reduce the quality of life of affected individuals and also cause significant economic loss in terms of increased error rates, reduced productivity, and diminished employment capability. The growing importance of fatigue in this society has stimulated a need to expand understanding of this debilitating symptom. Murine gammaherpesvirus-68 (MuGHV) infection in mice mimics many of the immunologic and pathophysiological features of Epstein-Barr virus (EBV) infection in people. The preliminary data indicate that infected mice develop fatigue and sleep perturbations that persist beyond the period of active (lytic) infection and can be exacerbated by stress. We will use this model to delineate the characteristics and mechanisms of chronic post-infective fatigue by completing the following Specific Aims: 1) quantify and assess sleep and the development of fatigue in mice infected with MuGHV a) during active and latent phases of infection, b) after secondary immunologic challenge with bacterial and viral products, and c) after deletion of IFN-gamma; 2) quantify and assess the impact of disruptive life events on fatigue and viral reactivation in mice with latent MuGHV infections a) in response to social stress, sleep loss, and exercise, and b) after deletion of IFN-gamma. In both Aims, measure associated changes in viral reactivation from latency and sleep-modulatory cytokines in specific brain regions and peripheral organs, and in viral reactivation in spleen and lung. These questions will be addressed as a function of mouse genetic background, mouse gender, and diurnal and post-infection timing. Creating a model system to support the delineation of mechanisms that generate post-infective fatigue establishes an essential foundation for the development of interventions that will prevent or alleviate this disabling disease outcome. Such a long-term result would improve the quality of life and economic welfare of target populations that span many disease conditions. Public Health Significance: Many people suffer chronically from a wide variety of disorders that require long-term or life-long medical management. These diseases, whose causes can be infectious (e.g., viral hepatitis, human immunodeficiency virus, herpesviruses) or non-infectious (e.g., renal failure, autoimmune diseases, cancer), and their associated therapies, are often associated with fatigue, non-restorative sleep, and excessive daytime sleepiness. Growing numbers of individuals also suffer from debilitating chronic fatigue of unknown cause. Excessive sleepiness and fatigue, particularly when persistent, reduce the quality of life of affected individuals and also cause significant economic loss in terms of increased error rates, reduced productivity, and diminished employment capability. The growing importance of fatigue in this society has stimulated a need to expand understanding of this debilitating symptom. Identifying the mechanisms that generate chronic fatigue and excessive daytime sleepiness and developing effective interventions for these disabling problems could improve the economic welfare and quality of life of many individuals. Nevertheless, conducting the appropriate and necessary studies in humans is difficult for many reasons. Progress in this area would be greatly facilitated by the development of a valid animal model. We propose to study murine gammaherpesvirus-68 (MuGHV) infection in mice as a model condition for human post-infective fatigue. MuGHV in mice mimics many of the immunologic and pathophysiological features of infectious mononucleosis, or mono, in people. Creating a valid model system for studying the causes of fatigue during these viral infections will establish a foundation for the discovery and development of treatments to prevent or alleviate this disabling disease outcome in people. Such a long-term result would improve the quality of life and economic welfare of target populations that span many disease conditions.